Heat shock proteins (hereafter HSP) are chaperone proteins which regulate the conformational stability and maturation of many cellular proteins. Numerous HSP's are known and are classified according to their molecular weight. HSP90 is a 90 k Dalton protein chaperone that plays a central role in regulating, for example, protein homeostasis. HSP90 regulates the stability of certain proteins (“client proteins”) and maintains them in the appropriate three-dimensional conformation so they can perform their cellular functions. In humans, there are two HSP90 isoforms in the cytosol, HSP90α and HSP90β. These proteins are closely related and, to date, no differences in their activities have been identified.
In addition to normal cellular function, certain HSP90 client proteins are associated with abnormal cellular function. For example many of the proteins stabilized by HSP90 are oncoproteins and cell-signalling proteins important in cancer cell proliferation and cancer cell survival, including many kinases and transcription factors including, but not limited to ErbB2, Raf-1, Akt/PKB, mutant p53, v-src, c-src, MEK, Focal adhesion kinase (FAK), P210bcr-abl, CDK4 and Epidermal growth factor receptor (EGFR).
Accordingly, HSP90 has been implicated in cancer, and other diseases. HSP90 is therefore an important target for drugs that inhibit the function of HSP90 and its role in diseases such as cancer.
HSP90 is over expressed in cancer cells and is thought to be involved in various cellular processes, such as cell proliferation, differentiation and apoptosis. Inhibition of HSP90 is expected to result in the blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic HSP90 client proteins, therefore HSP90 inhibitors are expected to provide broad-spectrum antitumour activity.
The anti-cancer effects of HSP90 inhibition have been demonstrated both in vitro and in vivo for a variety of different hematologic and solid tumours including multiple myeloma (Vilenchik et al., Chem & Bio, 2004 Jun. 11, 787-797; Solit et al., Clin Can Res, 2002 May, 8, 986-993, Beliocoff et al., Anticancer Drugs 2004 August; 15 (7):651-62; Bagatel et al., Molecular Cancer Therapeutics, 2004 August; 3 (8):1021-30; and Cullinan et al., Seminars in Oncology, 2006 August; 33 (4):457-65).
HSP90 inhibitors may be useful in the treatment of other disorders, for example inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders and metabolic diseases.
Various HSP90 inhibitors are known. The benzoquinone ansamycin antibiotic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and derivatives thereof are currently in clinical trials an anticancer agent in patients with solid tumour disease.
WO 03/037860 discloses certain purine derivatives as HSP90 inhibitors.
WO 2005/021552 discloses certain pyrimidothiophene derivatives as HSP90 inhibitors.
WO 2005/028434 discloses certain pyrimidine derivatives as HSP90 inhibitors.
WO 2006/117669 discloses certain resorcinol pyrimidine derivatives as HSP90 inhibitors.
WO 2006/122631 discloses certain quinazoline derivatives as HSP90 inhibitors.
WO 2006/105372 discloses certain alkynyl pyrrolo[2,3-d]pyrimidine derivatives as HSP90 inhibitors.
WO 2007/035963 discloses certain heterocyclic compounds, such as 2-aminopurines, pyrazolopyrimidines, pyrrolopyrimidines, alkynyl pyrrolopyrimidine and triazopyrimidines as HSP90 inhibitors.
WO 2007/092496 discloses certain 7,9-dihydropurin-8-one compounds as HSP90 inhibitors.
Kasibhatla et al. (J. Med. Chem., 2007, 50 (12), 2767-2778) discloses certain purine derivatives as HSP90 inhibitors.
There remains, however, a need to develop alternative HSP90 inhibitors.